Aldosterone is a steroid hormone secreted in the adrenal cortex. In primary cells of the distal tubules and collecting ducts of the kidney, aldosterone binding to the mineralocorticoid receptor (MR) results in the retention of sodium and water and excretion of potassium, which in turn leads to increased blood pressure. Aldosterone also causes inflammation that leads to fibrosis and remodeling in the heart, vasculature and kidney. This inflammation may proceed by MR-dependent as well as MR-independent mechanisms (Gilbert, K. C. et al., Curr. Opin. Endocrinol. Diabetes Obes., vol. 17, 2010, pp. 199-204).
Mineralocorticoid receptor antagonists (MRAs), such as spironolactone and eplerenone, have been used previously to block the effects of aldosterone binding to MR. When given in addition to standard therapies such as angiotensin-converting enzyme (ACE) inhibitors and loop diuretics, the nonselective MRA spironolactone and the selective MRA eplerenone significantly reduced morbidity and mortality in patients with heart failure or myocardial infarction (Pitt, B. et al., New Engl. J. Med., vol. 341, 1999, pp. 709-717; Pitt, B. et al., New Engl. J. Med., vol. 348, 2003, pp. 1382-1390). However, the nonselective MRA spironolactone can also bind to and act at other steroid receptors, and as a consequence its use is associated with sexual side effects such as gynecomastia, dysmenorrhoea and impotence (Pitt, B. et al., New Engl. J. Med., vol. 341, 1999, pp. 709-717; MacFadyen, R. J. et al., Cardiovasc. Res., vol. 35, 1997, pp 30-34; Soberman, J. E. et al., Curr. Hypertens. Rep., vol. 2, 2000, pp 451-456). Additionally, both spironolactone and eplerenone are known to cause elevated plasma potassium levels (hyperkalemia) and elevated aldosterone levels.
An alternative method of blocking the effects of aldosterone is to inhibit its biosynthesis. CYP11B2 is a mitochondrial cytochrome P450 enzyme that catalyzes the final oxidative steps in the conversion of 11-deoxycorticosterone, a steroidal precursor, to aldosterone (Kawamoto, T. et al., Proc. Natl. Acad. Sci. USA, vol. 89, 1992, pp. 1458-1462). Compounds that inhibit CYP11B2 should thus inhibit the formation of aldosterone. Such compounds, particularly those of nonsteroidal structure, should provide the beneficial effects of MRAs, without the adverse effects derived from steroid receptor binding or MR-independent inflammatory pathways. The art has recognized that reducing aldosterone levels by inhibiting aldosterone synthase could represent a new pharmaceutical strategy that might be useful in treating a disorder or disease characterized by increased stress hormone levels and/or decreased androgen hormone levels in a patient (WO2011/088188 to Novartis). Compounds possessing this activity might be expected to treat disease states such as heart failure, cachexia, acute coronary syndrome, Cushing's syndrome or metabolic syndrome.
CYP11B1 is a related enzyme that catalyzes the formation of glucocorticoids, such as cortisol, an important regulator of glucose metabolism. Because human CYP11B2 and CYP11B1 are greater than 93% homologous, it is possible for nonselective compounds to inhibit both enzymes (Kawamoto, T. et al., Proc. Natl. Acad. Sci. USA, vol. 89, 1992, pp 1458-1462; Taymans, S. E. et al., J. Clin. Endocrinol. Metab., vol. 83, 1998, pp 1033-1036). It would be preferable, however, for therapeutic agents to selectively inhibit CYP11B2 and the formation of aldosterone with diminished inhibition of, or affect on, CYP11B1 and the production of cortisol.
WO 2009/135651 to Elexopharm describes 6-pyridin-3yl-3,4,-dihydro-1H-quinolin-2-one derivatives as being CYP11B2 inhibitors. Two compounds described therein are lactam derivatives of the formula:
Structurally similar lactam and thiolactam compounds are disclosed by Lucas et al., J. Med. Chem. 2008, 51, 8077-8087; those compounds are said to be potential inhibitors of CYP11B2. Lucas et al. in J. Med. Chem. 2011, 54, 2307-2309 describes certain pyridine substituted 3,4-dihydro-1H-quinolin-2-ones as being highly potent as selective inhibitors of CYP11B2. An abstract of a dissertation reports that a series of novel heterocyclic-substituted 4,5-dihydro-[1,2,4]triazolo[4,3a]quinolones was evaluated for its aldosterone synthase activity; one of the compounds is reported as exhibiting excellent selectivity of CYP11B2 over CYP11B1. See WO2012/034417 and WO2013/151876.
The art recognizes benzimidazole derivates to be useful in treating various disease states. For example, WO 2012/012478 to Merck, Sharp & Dohme describes benzimidazole compounds as having the ability to CYP11B2. U.S. Pat. No. 6,897,208 to Aventis Pharmaceuticals describes a series of benzimidazole compounds as possessing utility as kinase inhibitors.
Novartis in US 2010/0261698 A1 describes indole derivatives of the formula:
Novartis indicates that these compounds inhibit aldosterone synthase and may be useful in the treatment of disease states such as heat failure and hypertension. In WO2010/130796 and WO2011/061168, Novartis discloses aryl-pyridine derivatives that are said to inhibit aldosterone synthase.
US 2009/0221591 A1 to Universitat des Saarlandes also discloses compounds that inhibit CYP11B1 and CYP11B2. WO 2009/135651 to Universitat des Saarlandes teaches that compounds of the formula:
possess the ability to inhibit aldosterone synthase.
Other publications that describe compounds which selectively inhibit CYP11B2 include WO2013/043518, WO2013/043520, and WO2013/04532, all to Merck Sharp & Dohme.
U.S. Pat. No. 7,381,825 to Takeda describes histone deacetylase inhibitors of the formulaZ-Q-L-Mwhere Q is a substituted or unsubstituted aromatic ring, L is a substituent providing between 0-10 atoms separation between M and the remainder of the compound, M is a substituent capable of complexing with a deacetylase catalytic site and/or metal ion, and Z is list of bicyclic groups, including, but not limited to:
where X is CR12 or N. These compounds are said to be useful in treating cell-proliferative diseases such as, for example, leukemia, melanoma, bladder cancer, etc.
Indazoline compounds are known in the art to be useful as pharmaceutical agents or as intermediates. U.S. Pat. Nos. 7,728,030 and 8,030,340 to AstraZeneca and Bayer Schering Pharma disclose a series of indazolyl ester or amide derivatives and indicate that these compounds have the ability to modulate the glucocorticoid receptor. Both patents disclose 5-iodo-1-(3-pyridyl)-1H-indazole as an intermediate. US 2010/0197678 to Boehringer Ingelheim USA discloses different indazole compounds possessing the ability to modulate the glucocorticoid receptor and teaches 5-bromo-1-(3-pyridyl)-1H-indazole as an intermediate used to make one of those compounds.
US 2009/0124607 A1 to AstraZeneca discloses a series of indazole-substituted sulfonamides that are said to be glucocortocoid receptor modulators, having utility in treating inflammatory diseases. The printed publication teaches 4-bromo-1-(3-pyridyl)-1H-indazole and 4-bromo-1-(5-methoxy-3-pyridyl)-1H-indazole as intermediates.
US 2004/0236110 A1 to Bayer Pharmaceutical Corp. describes a series of substituted 3-pyridyl indoline and indazoline compounds, which are said to be inhibitors of lyases and useful in treating various cancers; e.g., prostate or breast cancer. The printed publication teaches 5-bromo-1-(3-pyridyl)-1H-indazole and 5-bromo-1-(4-methyl-3-pyridyl)-1H-indazole as intermediates used to make some of those pyridyl indazole compounds.
Other indazole compounds are know in the art as intermediates. Anderson et al. in Angew. Chem., Int. Ed. 45(39), 6523-27 (2006) teach 1-(3-pyridyl)-1H-indazole and 5-(1H-indazol-1-yl)-3-pyridinecarbonitrile as intermediates. Abby PharmaTech, LLC is said to sell 1-(3-pyridyl)-1H-indazol-5-ol. Ukrorgsyntez Ltd. is said to be a supplier for 1-(6-chloro-2-pyrazinyl)-1H-indazole.